ABSTRACT The majority of research on early Alzheimer's disease (AD) has focused on cognition and has overlooked the possibility that changes in emotion may be one of AD's first manifestations. Molecular positron emission tomography (PET) scans detect elevated uptake of beta amyloid and tau, proteins that are neuropathological hallmarks of AD, in living patients with AD and in those with mild cognitive impairment (MCI), the clinical phase that precedes AD. An amyloid positive (amyloid+) PET scan in cognitively normal adults indicates preclinical AD, a phase that may begin years or decades before cognitive symptoms emerge. In addition to cognitive deficits, alterations in emotion are also common in MCI and AD and reflect changes in the neural systems that support emotion generation and emotion regulation. Declining emotion regulation may signify a pathological aging process and the presence of incipient neurodegenerative changes. Laboratory studies of emotion physiology and behavior have the potential to uncover the biological basis of affective change in AD and to determine how and when AD emotion trajectories diverge from those of normal aging. Individual differences in biological variables including sex and genetics (AD risk factor Apolipoprotein ?4 as well as single nucleotide polymorphisms and gene expression profiles) may modify disease progression or relate to variability in emotion functioning over time. The overall goal of the proposed project is to elucidate the neural systems and genetic factors that underlie emotion change in AD. Anatomically-specific markers of emotion could be used to broaden current conceptualizations of early AD phenotypes, identify subtypes at greatest risk for affective symptoms, monitor symptom progression, or track disease-related decline in clinical trials of asymptomatic or mildly symptomatic individuals. We will conduct a longitudinal study of 200 participants: 50 amyloid negative healthy controls, 50 amyloid+ healthy controls, 50 amyloid+ patients with MCI, and 50 amyloid+ patients with AD. Participants will undergo baseline genetic analyses as well as laboratory assessments of emotion (i.e., autonomic nervous system reactivity, facial expression, and subjective experience) and magnetic resonance imaging at three annual research visits. The central hypothesis of this proposal is that emotion dysregulation is an early feature of AD that can be assessed via objective measures of physiology and behavior, direct readouts of emotion systems. We will address three key aims. In Aim 1, we will determine how early AD emotion trajectories diverge from those of normal aging. In Aim 2, we will identify how emotion circuit decline relates to decreasing emotion regulation over time. In Aim 3, we will examine how sex and genetic variation relate to individual differences in emotion across the AD continuum. This project has the potential to advance current models of the neurobiological basis of emotion change in early AD.